The primary objective of this proposal is to test the hypothesis that EBV is associated with a clinical illness which can be differentiated from infectious mononucleosis. To this end, patients who have had varying combinations of pharyngitis, lymphadenopathy, headache, fatigue, myalgia, arthralgia, neuralgia, paresthesis, depression and dyslogia for over two years, and four controls--unrelated individuals but age- and sex-matched with and without histories of typical infectious mononucleosis; individuals with similar symptoms, but whose anti-EBV titers fall below the case definition; symptomatic individuals who are seronegative for EBV; and one corollary study group consisting of case family members will be followed for one year. Symptom scores, family history records, antibody titers to EBV antigens, adenovirus, herpes zoster, influenza A, herpes simplex, cytomegalovirus, Mycoplasma pneumoniae and EBV virus excretion will be measured. The latter tests consist of incubation of subject salivary secretion with adult B-lymphocytes, EBV viral DNA hybridization studies using pharyngeal epithelial cells and circulating B-lymphocytes, induction of early antigen in Raji cells by patient salivary secretions, and establishment of spontaneous lymphoid cell lines from peripheral blood lymphocytes. Lymphocytes will also be stained for EBNA and VCA. Sera from all subjects will also be evaluated for antibodies to products of EBV gene fragments (BAM HI K) and a peptide derived from the Epstein-Barr nuclear antigen. Immune responses known to be important during resolution of EBV infection will be examined: in vitro inhibition of immunoglobulin secretion, limiting dilution analysis of spontaneous B-cell proliferation, and natural killer cell activity. In vitro generation of interferon alpha and interferon gamma and interleukin-2 will not be studied as originally proposed. Data from each portion of the study will be analyzed to determine differences between/among patient and control groups. It is hoped that this study will confirm that EBV is associated with readily recognizable clinical illness; a relationship which has probably existed for a long time, but which has not been readily apparent. Recognition would allow a specific diagnosis for patients who may have had other labels applied to their disease and serve as a stimulus for further research into this likely common illness.